{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T02:30:36Z","timestamp":1792290636374,"version":"4.4.0"},"reference-count":251,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T00:00:00Z","timestamp":1760227200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI158694"],"award-info":[{"award-number":["R01AI158694"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cardiac inflammation and hypertrophy develop as a pathologic response to an array of insults, such as myocardial infarctions, chronic systemic hypertension, and valvular defects. Due to the high prevalence of such conditions, there is an increasing need to prevent and halt cardiac hypertrophy. Because cardiac damage and subsequent remodeling can lead to arrhythmias, heart failure, and even sudden cardiac death, inhibition of cardiac hypertrophy is key to reducing cardiovascular-related mortality. The immune system is the driving force behind inflammatory reactions. All three pathways of complement system activation\u2014classical, lectin, and alternative\u2014are implicated in developing cardiac damage, inflammation, and hypertrophy due to infectious and non-infectious causes, autoimmune diseases, genetic polymorphisms, and forms of complement dysregulation. Of interest in this review is the role of the complement system, a collection of soluble and membrane-bound proteins that mediate inflammatory processes through interactions with signaling molecules and immune cells. This review comprehensively discusses the roles of these complement pathways in contagious, chronic inflammatory, genetic, and metabolic diseases. An overview of the completed and terminated clinical trials aimed at preventing cardiovascular mortality by targeting various aspects of the complement system and inflammatory reaction is included. Most current treatments for cardiac inflammation and remodeling primarily target the renin\u2013angiotensin\u2013aldosterone system (RAAS), which prevents further remodeling by reducing myocardial workload. However, moving forward, there may be a place for emerging anti-complement therapeutics, which impair the inflammatory response that generates hypertrophy itself.<\/jats:p>","DOI":"10.3390\/ijms26209931","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T16:13:03Z","timestamp":1760717583000},"page":"9931","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Functional Roles of the Complement Immune System in Cardiac Inflammation and Hypertrophy"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-8335-7617","authenticated-orcid":false,"given":"Kathryn D.","family":"Hok","sequence":"first","affiliation":[{"name":"Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine for Prevention of Human Diseases, UTHealth-McGovern Medical School, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haydn E.","family":"Rich","sequence":"additional","affiliation":[{"name":"Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine for Prevention of Human Diseases, UTHealth-McGovern Medical School, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6282-1427","authenticated-orcid":false,"given":"Anthony","family":"Shadid","sequence":"additional","affiliation":[{"name":"Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine for Prevention of Human Diseases, UTHealth-McGovern Medical School, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lavanya","family":"Gunamalai","sequence":"additional","affiliation":[{"name":"Center for Human Genetics, The Brown Foundation Institute of Molecular Medicine for Prevention of Human Diseases, UTHealth-McGovern Medical School, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6041-4788","authenticated-orcid":false,"given":"Tingting","family":"Weng-Mills","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, UTHealth-McGovern Medical School, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8452-2903","authenticated-orcid":false,"given":"Rajarajan A.","family":"Thandavarayan","sequence":"additional","affiliation":[{"name":"Department of Cardiology, DeBakey Heart & Vascular Center, Houston Methodist Weill Cornell Medical College, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nirmal K.","family":"Banda","sequence":"additional","affiliation":[{"name":"Division of Rheumatology-Department of Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Francoise","family":"Doursout","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, UTHealth-McGovern Medical School, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9107-3405","authenticated-orcid":false,"given":"Marcos I.","family":"Restrepo","sequence":"additional","affiliation":[{"name":"VA-San Antonio Geriatric Research Education and Clinical Center (GRECC)-South Texas Veterans Health Care System Audie L. Murphy Division, UTHealth San Antonio, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pooja","family":"Shivshankar","sequence":"additional","affiliation":[{"name":"Center for Metabolic and Degenerative Diseases, The Brown Foundation Institute of Molecular Medicine for Prevention of Human Diseases, UTHealth-McGovern Medical School, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1038\/s41569-018-0007-y","article-title":"Mechanisms of physiological and pathological cardiac hypertrophy","volume":"15","author":"Nakamura","year":"2018","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Bazgir, F., Nau, J., Nakhaei-Rad, S., Amin, E., Wolf, M.J., Saucerman, J.J., Lorenz, K., and Ahmadian, M.R. (2023). 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